Ppar gamma agonists for treatment of multiple sclerosis

ABSTRACT

Methods of treatment of multiple sclerosis (MS) with PPARγ agonists, and in particular with the compound of formula (I) known as INT131:

FIELD OF INVENTION

The present invention relates to methods of treatment of multiplesclerosis (“MS”).

BACKGROUND OF THE INVENTION

Multiple sclerosis or MS is a disease that affects the brain and spinalcord resulting in loss of muscle control, vision, balance, sensation(such as numbness) or thinking ability.

In MS, parts of the brain and spinal cord, which together form thecentral nervous system or CNS are recognized as being foreign and areattacked by one's own immune system. At the cellular level, the CNS ismade up by neurons, the “thinking cells” of the nervous system, andglial cells, which perform a wide variety of vital functions. The cellbodies of the neurons are connected to one-another by axons, whichfunction like wires tying neuronal networks together. There are billionsof axons in the CNS, which, like copper wires, need to be insulated toprevent loss of signaling, to boost the speed of signaling and toprevent signal interference. The insulating material of the CNS, calledmyelin, is a specialized organelle of glial cells, which wrap the myelinaround the axons. In MS, elements of myelin are recognized as foreign,and are attacked by the individual's own immune system. As a result ofthese immune attacks the myelin is destroyed, and often, the associatedaxons are also damaged leading to death. This is an iterative processbroken up by periods of remyelination. However, while myelin can reform,eventually the pool of cells that can make myelin is depleted, resultingin areas of chronic CNS demyelination that eventually form scars, alsoknown as plaques, and whose formation is known as sclerosis. When thisprocess of sclerosis is iterative, the resulting form of MS is calledrelapsing/remitting MS. There is also another rarer form of MS, calledprimary progressive MS, where no remission occurs. In either case,without the myelin, electrical signals transmitted throughout the brainand spinal cord are disrupted or halted. The affected areas of the brainthen become unable to properly send and to receive messages. It is thisbreakdown of communication that causes the symptoms of MS.

There are a variety of medications available that can reduce thefrequency and severity of MS symptoms in some people with MS. Symptomsmay be divided into three categories: primary, secondary, and tertiary.Primary symptoms are a direct result of the demyelination process. Thisimpairs the transmission of electrical signals to muscles (to allow themto move appropriately) and the organs of the body (allowing them toperform normal functions.) The symptoms include: weakness, tremors,tingling, numbness, loss of balance, vision impairment, paralysis, andbladder and bowel problems.

Secondary symptoms result from primary symptoms. For example, paralysis(a primary symptom) can lead to bedsores (pressure sores) and bladder orurinary incontinence problems can cause frequent, recurring urinarytract infections. These symptoms can be treated, but the ideal goal isto avail them by treating the primary symptoms.

Tertiary symptoms are the social, psychological, and vocationalcomplications associated with the primary and secondary symptoms.Depression, for example, is a common problem among people with MS.

The course of multiple sclerosis is highly variable. In particular, theearliest stages of the disease can be somewhat unpredictable. Because ofthis uncertainty, doctors often tell their patients that they “probably”or “possibly” have MS. Diagnosis is based on the combination of clinicalpresentations, findings on magnetic resonance imaging (“MRI”) and othertests, and patterns of recurrence. At present there is no way to predicthow each person's disease will progress. It often takes an extendedperiod of time before a definitive diagnosis of MS can be made. Thereare three main courses that MS takes:

Relapsing-remitting MS (“RRMS”): characterized by unpredictable acuteattacks, called “exacerbations,” with worsening of symptoms followed byfull, partial or no recovery of some function. These attacks appear toevolve over several days to weeks. Recovery from an attack takes weekssometimes months. The disease does not worsen in the periods between theattacks.

This pattern usually occurs early in the course of MS in most people.

Primary-progressive MS: characterized by a steady progression ofdisability, without any obvious relapses and remissions. This form ofdisease occurs in just 15% of all people with MS, but is more common inpeople who develop the disease after the age of 40.

Secondary-progressive MS: initially begins with a relapsing-remittingcourse, but later evolves into progressive disease. The progressive partof the disease may begin shortly after the onset of MS, or it may occuryears or decades later.

A true exacerbation of MS is caused by an area of inflammation (i.e.swelling) in the nerves of the brain and spinal cord system followed bysomething called demyelination, which is the destruction of myelin. Themyelin is the fatty sheath that surrounds and protects the nerve fibers.An exacerbation of MS may be mild and not cause a noticeable impairmentin functioning or may significantly interfere with a person's dailylife. Untreated, exacerbations can last from several days to severalweeks, although they may extend into months.

Current therapy intended to slow MS progression has many difficulties. Anumber of drugs have been shown to slow the progression of MS in somepeople. These drugs work by suppressing, or altering, the activity ofthe body's immune system. Thus, these therapies are based on the theorythat MS is, at least in part, a result of an abnormal response of thebody's immune system that causes it to attack the myelin surroundingnerves. While these disease modifying treatments have altered thenatural history of RRMS in many patients, they are non-curative and havesignificant adverse effects including the sequelae of systemicimmunosuppression, as well as fever, body pains, malaise, arthralgia,myalgias, flu-like symptoms, liver function test (LFT) elevations,activation of latent viruses, including John Cunningham (JC) virus,which leads to the oft-lethal Progressive Multifocal Leukoencephalopathy(PML), and more. As a result, the treatments are poorly tolerated by asignificant number of patients when given at therapeutic doses andbreakthrough disease activity is virtually a given. For the 30% ofpatients who are either non-responsive, or who have only partialdrug-responses (˜19%), or for those that do not tolerate therapeuticdosages of otherwise effective drug, there are very limitedalternatives. Examples include Avonex® (interferon beta-1a; Avonex is aregistered trademark of Biogen Idec MA Inc.), Betaseron® (interferonbeta-1b; Betaseron is a registered trademark of Bayer Pharma), Copaxone®(Glatiramer acetate; Copaxone is a registered trademark of TevaPharmaceutical Industries), Novantrone® (mitoxantrone; Novantrone is aregistered trademark of Immunex Corporation), Rebif® (interferonbeta-1a; Rebif is a registered trademark of Ares Trading), Tysabri®(natalizumab; Tysabri is a registered trademark of ElanPharmaceuticals), Tecfidera® (BG12; Tecfidera is a registered trademarkof Biogen Idec), Laquinimod™ (Laquinimod is a trademark of TevaPharmaceuticals) and Aubagio® (Teriflunomide; Aubagio is a registeredtrademark of Sanofi).

Other undesirable characteristics of these drug therapies includeunpleasantness, pain and discomfort associated with injections,leukopenia, opportunistic infections, nausea, vomiting, diarrhea,alopecia, flushing, high cost and drug instability. Accordingly, thereis still a need in the art for a safe and effective method for slowingthe progression, treatment and alleviating symptoms of MS.

The deterioration of these physical and cognitive functions can also bethe result of both neuroinflammation and gray matter loss that is partof the MS neuropathologic process. While immunomodulation and diseasemodification is partially achieved with the current first-line drugs,they do not provide overall neuroprotection which would be consideredthe holy grail of therapy.

SUMMARY OF THE INVENTION

It has now been discovered that PPARγ agonists are effective for MS.These compounds are agonists of the peroxisome proliferator-activatedreceptor γ (PPARγ). The PPARγ is a transcription factor belonging to thesteroid/thyroid/retinoid receptor superfamily. To date, PPARγ agonistshave been therapeutic agents for disorders such as obesity, diabetes anddyslipidemia.

In one aspect, the present invention provides methods of treating orpreventing MS relapses. The methods typically involve administering to asubject in need thereof a therapeutically effective amount of compoundsprincipally described in U.S. Pat. No. 7,601,841 and specifically onereferred herein below as INT131. INT131 is unique among PPARγ agonistsin that it is a selective activator of a highly limited number of PPARγpathways. Among these INT131-sensitive pathways are anti-inflammatoryand neuroprotective gene activation cascades.

BRIEF DESCRIPTION OF THE DRAWINGS

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawing(s) will be provided by thePatent and Trademark Office upon request and payment of the necessaryfee.

FIG. 1 is a photograph of brainstem cross-sections of INT131 treated anduntreated mice with arrows identifying infiltrating CD45-positiveleukocytes.

FIG. 2 is a graphical representation of the number of infiltratingCD45-positive leukocytes found in the brainstem of INT131 treated anduntreated mice.

FIG. 3 is a graphical representation of the bioavailability of INT131 inthe brain, spinal cord and CSF, relative to its bioavailability inblood.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the compound (I),

has been found to be unexpectedly effective for MS. This compound isalso known as INT131.

Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined.

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention” refer to a method ofdecreasing the probability or eliminating the possibility that a diseasewill be contracted.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

The term “subject” is defined herein to include animals such as mammals,including but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either net or in a suitable inertsolvent. Examples of pharmaceutically acceptable base addition saltsinclude sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either net or in a suitable inertsolvent. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isbutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumeric mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present inventions contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds may be registered by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In additional to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, be bioavailable by oral administrationwhereas the parent drug is not. The prodrug may also have improvedsolubility in pharmacological compositions over the parent drug. A widevariety of prodrug derivatives are known in the art, such as those thatrely on hydrolytic cleavage or oxidative activation of the prodrug. Anexample, without limitation, of a prodrug would be a compound of thepresent invention which is administered as an ester (the “prodrug”), butthen is metabolically hydrolyzed to the carboxylic acid, the activeentity. Additional examples include peptidyl derivatives of a compoundof the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are all intended to beencompassed within the scope of the present invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵1) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

EMBODIMENTS OF THE INVENTION

A new use of known compounds that modulate PPARγ has now beendiscovered.

The experimental autoimmune encephalomyelitis (“EAE”) model has beenshown to be a valid and accurate predictor of the effects of a compoundof treatment paradigm on MS in humans. As seen below, treatment withINT131 of animals with EAE with INT131, results in the subjects becomingand remaining mostly symptom-free. Accordingly, it is believed thatINT131 will be effective for the treatment of MS.

In particular, the compound (I),

has been found to be unexpectedly effective for MS.

This compound is also known as INT131.

We anticipate that 1-3 mg/day is likely to be a sufficient dose toelicit the desired response.

Example 1 INT131 Is a Potent Inhibitor of EAE Progression INT131 ReducesRelapse in Mouse Model

EAE is a well-characterized and widely used model of MS. It is one ofthe few animal models in which drug therapeutic activity in the modeloften mimics and anticipates the drug's effects in human disease. Inthis model, mice are immunized with well-defined antigenic fragments ofcentral nervous system myelin, such as fragments of the proteolipidprotein (PLP). Over the course of 2 to 3 weeks the immunized animalsdevelop a clinical and histopathologic syndrome of T-cell mediatedcerebral autoimmunity that is highly reminiscent of relapsing/remittingMS (RRMS). The similarities between EAE and RRMS include inflammatorycerebral infiltrated and accompanying Th1/Th17 responses to both thedisease initiating myelin PLP peptide, and subsequent epitope spread,seen in disease relapse.

The animals were immunized with the myelin peptide (PLP¹³⁹⁻¹⁵¹) and thespread epitope peptide (PLP¹⁷⁸⁻¹⁹¹) which drives disease relapse.Studies consisted of three experimental arms in which the mice weregiven daily ip injection of vehicle, or either 1 or 3 mg/kg/d of INT131.Following immunization, the animals underwent daily neurologicalevaluation by an experienced investigator. In these studies treatmentbegan at the time of the first remission.

INT131 treatment virtually blocks relapse. Following the expectedclinical disease peak at about two weeks post-immunization, symptomsbegan to ebb as the animals drifted into remission. All of the animalswere treated with INT131 on day 20. By the 22^(nd) day followingimmunization relapse began as expected, however, only in the vehicletreated animals. In contrast, the INT131 treated mice either continuedto improve slightly (1 mg/kg), or remained stable (3 mg/kg).

A comparison of relapse rate on the 25^(th) day post-immunizationdemonstrated a highly significant reduction in the relapse in bothINT131 treatment paradigms, as compared to the vehicle-treated subjects.Between 9 percent (1 mg/kg/d) and 16 percent (3 mg/kg/d) of theINT131-treated animals relapsed, as compared to 72 percent of thevehicle-treated mice. Among the INT131-treated animals that do relapse,the disease burden is exceptionally mild in comparison to the vehicletreated mice.

INT131 Mediates Leukocyte Clearance from the CNS

Initiating INT131 treatment during remission extends the time subjectsremain relapse-free, as compared to vehicle/placebo treatment. However,because there is little active neuroinflammation during remission, thisparadigm is not informative about the effects of INT131 on acuteneuroinflammation. To better understand the effects of INT131 on theacute inflammatory response we treated mice with EAE at the height ofthe clinical disease. As discussed above, this results in a rapidimprovement in clinical symptoms. Examination of neural tissue from micetreated with INT131 at the peak of disease demonstrates a paucity ofinfiltrating CD45-positive leukocytes in the INT131 treated tissue,compared to an exuberant leukocyte infiltration observed in neuraltissue from the vehicle-treated animals (FIGS. 1 and 2).

INT131 treatment was begun at the peak of disease (day 20) andbrainstems were harvested at day 32, and stained with αCD45 to identifyinfiltrating leukocytes. CD45 (also known as Leukocyte Common Antigen)is expressed on all hematopoietic cells except erythrocytes andplatelets, and is required for B- and T cell-receptor-mediatedactivation. Thus, CD45 is critical in mediating the inflammatoryprocess. As seen in FIG. 1, there are numerous CD45-expressing cells inthe tissue from the vehicle-treated subjects (arrows), while there arefew in either concentration of INT131-treated tissue. Quantitation ofthe number of CD45-positive leukocytes in the brain stems of animalstreated with INT131 at the peak of disease shows that drug treatmentresults in a paucity of infiltrating white cells 12 days after treatmentinitiation (FIG. 2). These findings unify the clinical and histologicalfindings that INT131 is a potent and effective treatment of acuteneuroinflammation in this model of RRMS.

Example 2 Bioavailability in the Central Nervous System

Background

The Blood Brain Barrier (“BBB”) is a physical/biochemical impedimentthat acts as a diffusion barrier and a physical sieve to impede theinflux of most macromolecules and blood-borne cells from entering thebrain. The BBB is formed by the physical interactions of the threedistinct cellular components that comprise it, including endothelialcells, astrocyte end-feet, and pericytes. The diffusion barrier functionof the BBB is dependent upon tight junctions that form between thecerebral endothelial cells, which selectively exclude most blood-bornesubstances from entering the brain. Ballabh, P. et al., The blood-brainbarrier: an overview: structure, regulation, and clinical implications,Neurobiol Dis, 2004, June, 16(1), 1-13. In the setting of acuteinflammation, as occurs during MS relapse, the BBB near the lesionbreaks down, allowing the influx of both immunomodulatory macromoleculesand leukocytes to the lesion site, which further drives the inflammatoryprocess forward. Minagar A. et al., Blood-brain barrier disruption inmultiple sclerosis, Multi Scler, 2003, Dec., 9(6), 540-549.

The acute inflammatory lesions in MS can be detected in real-time withthe use of contrast-enhanced MRI. Under normal homeostatic conditions,the BBB prevents the passage of gadolinium-based contrast medium intothe brain and spinal cord. However, at the sites of acute inflammation,the BBB is impaired, and gadolinium readily enters the lesion, where itis seen as a bright area in the MR image. Tourdias T. et al.,Neuroinflammatory imaging biomarkers: relevance to multiple sclerosisand its therapy, Neurotherapeutics, 2013, Jan., 10(1), 111-123. However,this process is short lived, with about 70% of the lesions excludinggadolinium within 30 days, owing to the reformation of the local BBB.Bastianello S. et al., Serial study of gadolinium-DTPA MRI enhancementin multiple sclerosis, Neurology, 1990, Apr., 40(4), 591-595; Smith M.E., et al., Clinical worsening in multiple sclerosis is associated withincreased frequency and area of gadopentetate dimeglumine-enhancingmagnetic resonance imaging lesions, Ann Neurol, 1993, May, 33(5),480-489. Therefore, if therapeutic compounds are to be effective overthe full course of RRMS, including the extended periods of remission, itis critical that a compound be able to cross the intact BBB that isrestored during remission. Correale J., et al., The blood-brain barrierin multiple sclerosis: functional roles and therapeutic targetingAutoimmunity, 2007, Mar., 40(2), 148-160.

Procedure

To test whether INT131 is able to penetrate the intact BBB INT131 wasradiolabeled with tritium (“[³H]INT131”), prior to intraperitonealinjection into adult Sprague-Dawley rats. The purity of the radiolabeledINT131 was determined by high-performance liquid chromatography (HPLC)fractionation prior to injection, and again at the close of theexperiment. At both time points virtually all of the radiolabeledmaterial was found in a single peak, demonstrating the stability of[³H]INT131 over the course of the study. At the time of injection intothe test animals, the labeled INT131 was mixed with non-labeled INT131such that the injection of 50 mg/kg of INT131 resulted in each animalreceiving 1000 μCi/kg of labeled drug. The test animals were sacrificedat 1, 6 and 24 hours after injection and blood, brain, cerebrospinalfluid (“CSF”), spinal cord, kidney, liver and small bowel were harvestedfor determination of [³H]INT131 content by liquid scintillography.

Results

Table 1 lists the INT131 concentration in all the tissues analyzed. Onehour after a single administration of ˜50 mg/kg of [³H]INT131, theaverage amount of INT131 in the neural compartments was less than 0.5μg/gram of brain tissue, which was approximately 10 fold less than thatfound in the circulation. In contrast, at 6 and 24 hours, the amount ofINT131 in the neural tissues had increased approximately 10 fold. Thisdelay in accumulation of drug in neural tissues is consistent with itsactive transport across the BBB.

The bioavailability of INT131 in the brain and spinal cord increasedover the course of 24 hours such that it was ˜10% the level found inblood 6 hours after injection, whereas by 24 hours, the level of INT131in neural tissues had increased to 25% of that found in the circulation(FIG. 3). The absolute amount of INT131 in the brain and spinal cord 1day after injection was over 4 μg/gram of wet neural tissue (see Table1). This is an amount of drug that is more than sufficient to saturatethe available PPARγ receptor. Lee DH, et al., Selective PPARγ modulatorINT131 normalizes insulin signaling defects and improves bone mass indiet-induced obese mice, Am J Physiol Endocrinol Metab, 2012, Mar. 1,302(5), E552-560. Separate analysis of the brain and spinal cord, whichtogether form the central nervous system, showed similar accumulation oflabeled INT131 at each time point analyzed, thereby serving as aninternal control on both the assay and the true distribution of thedrug. The timing and high levels of compound found in liver and gut arelikely the result of the known routes of INT131 metabolism andexcretion.

As shown in FIG. 3 and Table 1, there is a lag in the accumulation ofdrug in the CSF, relative to the brain and spinal cord, between 6 and 24hours. This finding is consistent with the known biology of the BBB. Thesolutes present in the CSF accumulate through active transport of thedrug from the choroid plexus to CSF, a relatively slow process. Thedelay in INT131 accumulation in the CSF, compared to the brain andspinal cord, further supports the conclusion of INT131 penetration ofthe blood-brain barrier.

TABLE 1 Distribution of INT131 in tissues at 1, 6 and 24 hours afteradministration. μg/gram wet weight 1 h 6 h 24 h Blood 4.048 41.80417.939 Brain 0.569 5.976 4.646 CSF 0.292 2.862 5.298 Spinal 0.478 4.8144.306 cord Kidney 7.732 32.851 15.429 Liver 24.393 140.84 36.36 Small19.711 222.98 34.456 bowel

Example 3 Neuroprotection

Cortical and subcortical gray matter atrophy are seen in all stages ofMS, however, thalamic loss has recently emerged as a sensitive andreliable marker of MS progression in the early stages of the disease. Itis expected that the addition of INT131 at either 1 or 3 mg will resultin sparing of thalamus from additional atrophy. INT131 would then be thefirst drug that clinically has demonstrated against gray matter atrophyin MS.

While this description is made with reference to exemplary embodiments,it will be understood by those skilled in the art that various changesmay be made and equivalents may be substituted for elements thereofwithout departing from the scope. In addition, many modifications may bemade to adapt a particular situation or material to the teachings hereofwithout departing from the essential scope. Also, in the descriptionthere have been disclosed exemplary embodiments and, although specificterms may have been employed, they are unless otherwise stated used in ageneric and descriptive sense only and not for purposes of limitation,the scope of the claims therefore not being so limited. Moreover, oneskilled in the art will appreciate that certain steps of the methodsdiscussed herein may be sequenced in alternative order or steps may becombined. Therefore, it is intended that the appended claims not belimited to the particular embodiment disclosed herein.

what is claimed is:
 1. A method of treating multiple sclerosis in apatient in need thereof comprising administering to said patient atregular dosing intervals of a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I),

or a pharmaceutically acceptable salt, prodrug, or isomer thereof
 2. Amethod of treating the symptoms of multiple sclerosis comprisingadministering to a patient in need thereof a compound of formula (I),

or a pharmaceutically acceptable salt, prodrug or isomer thereof
 3. Amethod of providing neuroprotection to a patient in need thereofcomprising administering a compound of the formula (I),

or a pharmaceutically acceptable salt, prodrug or isomer thereof
 4. Amethod of treating the symptoms of neuroinflammation comprisingadministering to a patient in need thereof a compound of formula (I),

or a pharmaceutically acceptable salt, prodrug or isomer thereof